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Radiation and the microenvironment – tumorigenesis and therapy

Key Points

  • Exposure to ionizing radiation increases the risk of developing cancer at low doses and is used to control cancer at high doses.

  • Ionizing radiation can elicit an 'activated' phenotype in some cells that promotes rapid and persistent remodelling of the extracellular matrix, through the induction of proteases and growth factors, as well as chronic production of reactive oxygen species.

  • The rapid and dynamic cell biology that occurs in irradiated tissues indicates the existence of a microenvironment-mediated damage-response programme. Some mechanisms of the ionizing radiation-induced microenvironment include chronic inflammation and persistent production of transforming growth factor-β.

  • These cellular and tissue responses to ionizing radiation can have non-targetted effects on non-irradiated cells, such as induction of genomic instability and neoplastic progression.

  • The functional consequences of exposing an organism to ionizing radiation are a product of DNA damage, cell loss and altered tissue microenvironments that promote carcinogenesis and might affect responses to anticancer therapies.

Abstract

Radiation rapidly and persistently alters the soluble and insoluble components of the tissue microenvironment. This affects the cell phenotype, tissue composition and the physical interactions and signalling between cells. These alterations in the microenvironment can contribute to carcinogenesis and alter the tissue response to anticancer therapy. Examples of these responses and their implications are discussed with a view to therapeutic intervention.

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Figure 1: Ionizing radiation, the microenvironment and cellular responses.

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Acknowledgements

Thanks to Noelle F. Metting for assistance with preparing Box 1.

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Correspondence to Mary Helen Barcellos-Hoff.

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DATABASES

Entrez Gene

epidermal growth factor

p53

TGFβ1

TGFβ3

National Cancer Institute

breast cancer

leukaemia

FURTHER INFORMATION

Cytokines Online Pathfinder Encyclopaedia – TGFβ

TGFβ signalling pathway

Washington State University Low Dose Radiobiology Programme

Glossary

IONIZING RADIATION

Energy from isotopic decay or produced by electromagnetic excitation that is capable of producing ionizations, directly or indirectly, while traversing matter.

CYTOKINES, GROWTH FACTORS AND CHEMOKINES

Proteins that convey information between cells, through secretion and interaction with receptors. Signalling by these molecules regulates cell proliferation, differentiation, motility, adhesion and apoptosis.

PARENCHYMA

Organ compartment that performs the function of a tissue — for example, tissue-specific epithelium.

STROMA

Organ compartment serving as the connective tissue framework; includes fibroblasts, immune defense cells and fat cells.

EXTRACELLULAR MATRIX

(ECM). An insoluble protein scaffold on which cells reside. The ECM provides the structure and attachment sites, and signals through cell surface receptors. Epithelial cells, endothelial cells and adipocytes rest on a specialized ECM called the basement membrane. Interstitial ECM is collagen-rich.

REACTIVE OXYGEN SPECIES

Highly reactive chemical radicals generated as products of oxygen degradation.

DIRECT EFFECTS

Interaction of energy with matter, resulting in ionization.

INDIRECT EFFECTS

Interaction of energy with water, resulting in production of reactive oxygen species.

X-RAYS

Sparsely ionizing radiation that has similar effects to γ-rays, and is used in radiotherapy. X-rays result from electron energy-transitions with the atom or through the deceleration of high kinetic-energy electrons.

γ-RAYS

Sparsely ionizing radiation that has similar effects to X-rays, and is used in radiotherapy. γ-Radiation results from excited and unstable nuclei of radioactive materials.

STEM-CELL NICHE

The restricted, specialized microenvironment that mediates stem-cell expansion and differentiation.

MARGINATION

Blood vessels outlined with cuffs of neutrophils.

CLASTOGENIC

Biological factors that increase markers of DNA damage such as mutation frequency, chromosome aberrations or sister chromatid exchange.

α-PARTICLES

Short range, high linear-energy transfer radiation from isotopic decay that gives rise to clusters of ionized molecules.

TISSUE REMODELLING

Activation process of extracellular matrix (ECM) degradation and production that affects the turnover and composition of ECM proteins. This process accompanies wound healing, inflammation and large scale apoptotic events, such as mammary gland involution. It can be induced by ionizing radiation, either subclinically or at a pathological level, preceding fibrosis.

ALLOGENEIC

When donor and recipient tissues share the same major histocompatibilty complex antigens.

SYNGENEIC

Genetically identical — for example, fully inbred mouse strains.

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Barcellos-Hoff, M., Park, C. & Wright, E. Radiation and the microenvironment – tumorigenesis and therapy. Nat Rev Cancer 5, 867–875 (2005). https://doi.org/10.1038/nrc1735

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